Cyclophosphamide
| 證據等級: L5 | 預測適應症: 5 個 |
目錄
Cyclophosphamide: From Cytotoxic Alkylating Agent to Myeloid Leukemia Treatment
One-Sentence Summary
Cyclophosphamide (DB00531) is a DNA-alkylating cytotoxic agent historically used across a wide range of malignancies and as a preparative conditioning regimen for haematopoietic stem cell transplantation (HSCT). The TxGNN model predicts it may be effective for Myeloid Leukemia — including acute myeloid leukemia (AML) — with 39 clinical trials and 20 publications currently supporting this direction. Evidence is primarily derived from its established role in myeloablative conditioning (e.g., the BuCy regimen) and post-transplant GvHD prophylaxis (PTCy), which together constitute one of the best-supported repurposing signals in this dataset.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Cytotoxic chemotherapy / HSCT myeloablative conditioning (no Canada DIN on file) |
| Predicted New Indication | Myeloid Leukemia (AML) |
| TxGNN Prediction Score | 99.47% |
| Evidence Level | L1 |
| Canada Market Status | Not marketed (0 DINs) |
| Number of DINs | 0 |
| Recommended Decision | Proceed with Guardrails |
Why Is This Prediction Reasonable?
Cyclophosphamide is a nitrogen mustard–class alkylating agent. Upon metabolic activation by hepatic cytochrome P450 enzymes (primarily CYP2B6), it generates phosphoramide mustard, which forms inter-strand DNA crosslinks that block replication and trigger apoptosis in rapidly dividing cells. Detailed formal MOA data from DrugBank is not available in this Evidence Pack; however, cyclophosphamide’s mechanism is extensively characterised in the published literature and is directly applicable to AML biology.
In the context of myeloid leukemia, cyclophosphamide is a backbone component of the BuCy (Busulfan + Cyclophosphamide) myeloablative conditioning (MAC) regimen used prior to allogeneic HSCT. This dual role — cytoreduction of residual leukemic blasts and creation of marrow space for donor engraftment — is mechanistically distinct from simple chemotherapy and explains why its therapeutic signal is so robust in AML. Post-transplant cyclophosphamide (PTCy), administered at high dose on days +3/+4 after transplant, further leverages its selective toxicity against alloreactive T cells to prevent graft-versus-host disease (GvHD), while preserving graft-versus-leukemia (GvL) activity.
AML and the classical indications for cyclophosphamide (lymphoma, multiple myeloma) share a common biological denominator: uncontrolled clonal proliferation of haematopoietic cells. The fact that multiple international Phase 3 RCTs — including the ongoing 700-patient pediatric AML trial (NCT02724163) — explicitly incorporate cyclophosphamide in their backbone regimens strongly validates TxGNN’s prediction and supports the L1 evidence rating.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02724163 | Phase 3 | Recruiting | 700 | International multicenter RCT comparing gemtuzumab ozogamicin doses added to cytarabine ± cyclophosphamide induction in children with AML; highest-level direct evidence |
| NCT00002534 | Phase 3 | Completed | N/A | Randomized trial of unmodified vs T-cell–depleted HLA-identical BMT for acute leukemias; cyclophosphamide is the conditioning backbone |
| NCT00152139 | Phase 3 | Completed | 33 | Matched unrelated donor PBSC or BM transplant for hematological malignancies including AML using cyclophosphamide-based conditioning |
| NCT01707004 | Phase 2 | Completed | 20 | Decitabine + TBI → BMT + high-dose cyclophosphamide for relapsed/refractory AML; direct endpoint data available |
| NCT00553202 | Phase 2 | Completed | 158 | KIR-incompatible unrelated donor HSCT for AML with monosomy 7, FLT3-ITD, or refractory/relapsed disease; cyclophosphamide in conditioning |
| NCT02094794 | Phase 2 | Active, not recruiting | 108 | Total marrow + lymphoid irradiation + cyclophosphamide + etoposide as conditioning for high-risk ALL/AML |
| NCT02294552 | Phase 2 | Completed | 200 | High-dose post-transplant cyclophosphamide as GvHD prophylaxis after allo-HSCT; risk-adapted single-agent vs combination strategy |
| NCT00849147 | Phase 2 | Completed | 55 | Non-myeloablative conditioning + haploidentical BMT (PTCy) for leukemia/lymphoma; effective GvHD suppression with preserved GvL |
| NCT05115630 | Phase 2 | Completed | 24 | “Off-the-shelf” NK cell (KDS-1001) + allo-SCT to decrease AML/MDS/CML relapse; cyclophosphamide as lymphodepletion agent |
| NCT03766126 | Phase 1 | Active, not recruiting | 22 | Anti-CD123 CAR-T (lentivirally transduced) for relapsed/refractory AML; cyclophosphamide used for standard lymphodepletion pre-infusion |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 40434956 | 2025 | RCT / Multi-centre comparative | Future Oncology | BuCy vs FluBu myeloablative conditioning for allo-HSCT in AML: BuCy is the historical standard; FluBu shows similar efficacy with less toxicity |
| 36357773 | 2023 | Systematic review / Network meta-analysis | Bone Marrow Transplantation | Bayesian network meta-analysis of MAC regimens (including BuCy) in adult AML undergoing allo-HSCT in complete remission; optimal regimen remains context-dependent |
| 38499049 | 2024 | Phase 2 / Prospective cohort | Transplant Immunology | Cladribine + busulfan + cyclophosphamide as intensive conditioning for R/R AML prior to allo-HSCT; demonstrates feasibility and efficacy |
| 29039989 | 2017 | Prospective case series | Pediatric Hematology and Oncology | Clofarabine + cyclophosphamide + etoposide in 17 children with R/R AML: 41% overall response rate including 4 CRs |
| 33325761 | 2021 | Retrospective cohort | Leukemia & Lymphoma | High-dose cyclophosphamide (60 mg/kg) for cytoreduction in AML with hyperleukocytosis (WBC ≥50×10⁹/L): rapid WBC reduction with manageable toxicity in 27 patients |
| 31628924 | 2020 | Retrospective comparative | Hematol Oncol Stem Cell Ther | BuCy vs BuFlu myeloablative conditioning for allo-HCT in AML/MDS: comparable survival outcomes; quality-of-life differences noted |
| 35955881 | 2022 | Retrospective cohort | Int J Mol Sci | PTCy after matched sibling/unrelated donor HSCT in pediatric AML: first published data in this specific population; acceptable GvHD rates and survival |
| 38466265 | 2024 | Retrospective cohort | Cytotherapy | Prognostic factors in haploidentical HSCT with PTCy for AML: large multi-centre EBMT-based analysis confirming PTCy safety and efficacy |
| 39939431 | 2025 | Retrospective cohort | Bone Marrow Transplantation | 1,823-patient EBMT analysis: impact of MAC vs RIC conditioning intensity on transplant outcomes in AML patients receiving PTCy-based GvHD prophylaxis |
| 40905088 | 2026 | Retrospective cohort | Haematologica | Genetic risk classification in 217 AML patients undergoing allo-HCT with MAC + PTCy: 2-year OS 77%, EFS 72%; strong evidence for PTCy efficacy across genetic risk categories |
Cytotoxicity
Cyclophosphamide is an antineoplastic alkylating agent (nitrogen mustard class) with well-established cytotoxic properties.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic — alkylating agent (nitrogen mustard / oxazaphosphorine class) |
| Myelosuppression Risk | High — dose-dependent leukopenia, neutropenia, and thrombocytopenia are the primary dose-limiting toxicities, especially at myeloablative doses (e.g., 60–120 mg/kg); nadir typically at days 7–14 |
| Emetogenicity Classification | Moderate to High — particularly at intravenous doses ≥1,000 mg/m²; antiemetic prophylaxis (NK1-RA + 5-HT3-RA + dexamethasone) required |
| Monitoring Items | CBC with differential (at least twice weekly during induction); serum creatinine and electrolytes; liver function tests (LFTs); urinalysis for haematuria (haemorrhagic cystitis risk) |
| Handling Protection | Must follow cytotoxic drug handling regulations — PPE (gloves, gown, eye protection), closed-system drug transfer devices for preparation; hazardous waste disposal required |
Additional notes: Haemorrhagic cystitis (caused by urinary metabolite acrolein) can be prevented with adequate hydration and MESNA co-administration, especially at doses >1 g/m². Cardiac toxicity is possible at very high doses (>100 mg/kg).
Safety Considerations
Formal TFDA/Health Canada package insert warnings and contraindications data are not available in this Evidence Pack. Based on the evidence retrieved:
- Drug Interactions: No DDI data was identified in this dataset. Cyclophosphamide is metabolised primarily by CYP2B6 and to a lesser extent CYP3A4; clinically significant interactions with CYP2B6 inducers (e.g., rifampin) and inhibitors are expected.
Please refer to the approved package insert for complete warnings, contraindications, and drug interaction information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Cyclophosphamide in myeloid leukemia is supported by the strongest available evidence tier (L1), with at least one ongoing 700-patient international Phase 3 RCT and a completed Phase 3 randomised trial, multiple Phase 2 completions, and 20 peer-reviewed publications including systematic reviews and RCTs. Its use in AML-directed HSCT conditioning (BuCy) and as post-transplant GvHD prophylaxis (PTCy) is internationally recognised and guideline-endorsed.
To proceed, the following is needed:
- Canada regulatory filing: No DINs currently exist in Canada; a New Drug Submission or supplemental NDS specifying the AML/HSCT indication would be required
- MOA data supplement: Retrieve full DrugBank MOA profile (CYP2B6 activation pathway, phosphoramide mustard mechanism) to complete mechanistic documentation
- Safety data supplement: Download and parse the TFDA and Health Canada monograph PDFs to populate key warnings, contraindications, and DDI profile
- Indication sub-classification: “Myeloid leukemia” encompasses AML, CML, and MDS with varying treatment paradigms — define the precise target indication (e.g., AML in HSCT-eligible patients, AML with hyperleukocytosis, PTCy GvHD prophylaxis) before advancing
- Comparator benchmarking: Compare BuCy vs BuFlu (fludarabine-busulfan) positioning, given that FluBu may offer comparable efficacy with reduced toxicity per the 2025 literature
YMYL Disclaimer: This report is for research reference only and does not constitute medical advice. All drug repurposing candidates require prospective clinical validation before clinical application.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.